3-Amino-1,2,4-benzotriazines are heterocyclic compounds that have diverse applications in the both the agrochemical and pharmaceutical industries. These compounds were originally found to have antimicrobial activity (DE 2204574; DE 2740887; and U.S. Pat. Nos. 3,980,779; 3,868,371; 3,991,189; 3,957,799 and 4,001,410) and have since been shown to have herbicidal (DD 272591; Henrie, et al. (1993) Quant. Struct. Act. Relat. 12:27–37), antimalarial (Horner and Henry (1968) J. Med. Chem. 11:946–949), human blood reology regulant (Boehme (1988) Med. Reihe 37:123–124), antifungal (Reich, et al. (1989) J. Med. Chem. 32:2474–2485), and antiinflammatory and analgesic (Regan, et al. (1980) J. Pharm. Sci. 69:798–793) activities. Of particular interest are the 3-amino-1,2,4-benzotriazine oxide derivatives that are used as radiosensitizers and selective cytotoxic agents for the treatment of tumors (U.S. Pat. No. 6,362,184; WO 01/46162; WO 89/08647; WO 91/04028; Dorie and Brown (1993) Cancer Res. 53:4633–4636; Kelson, et al. (1998) Anti-Cancer Design 13:575–592; Brown (2000) Molecular Medicine Today 6:157–162; Denny and Wilson (2000) Expert Opinion on Invest. Drugs 9:2889–2901).
Common methods for the synthesis of 3-amino-1,2,4-benzotriazines include the thermal reaction of 2-nitroaniline with cyanamide (Mason and Tennant (1970) J. Chem. Soc. 911), the base-induced cyclization of 2-nitrophenylurea followed by treatment with phosphoryl chloride and gaseous ammonia (Arndt (1913) Chem. Ber. 46:3522), and the addition of disodiocyanamide to benzofuroxan followed by acidic workup (U.S. Pat. No. 3,980,779; Seng and Ley (1972) Angew. Chem., Int. Ed. Engl. 11:1009). Alternative steps may include, for example, peracid oxidation of the parent monoxide of 1,2,4-benzotriazine to produce the dioxide (Robbins, et al, (1957) J. Chem. Soc. 3186; Mason, et al, (1970) J. Chem. Soc. B 911) and monoxide preparation by controlled reduction of the corresponding dioxide (Mason, et al, (1970) J. Chem. Soc. B 911; Wolf, et al. (1954) J. Am. Chem. Soc. 76:355). 3-Amino-1,2,4-benzotriazines may also be prepared by cyclization of formazan precursors using BF3/AcOH (Atallah and Nazer (1982) Tetrahedron 38:1793). Furthermore, o-fluoronitrobenzenes may be reacted for 4–6 hours with free guanidine base at 60° C. in t-BuOK/THF (Suzuki and Kawakami (1997) Synthesis 855) to produce these compounds.
The disadvantage of many of these methods is the production of halide wastes, acid byproducts, and the use of highly toxic corrosive substances at high temperatures. Given the commercial potential of 3-amino-1,2,4-benzotriazines, a need exists for a practical, safe, high yielding, and direct synthetic process for the manufacture of such compounds.